Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): identification and characterization of a mechanism-based inactivator.
Inhibition on human liver cytochrome P450 3A4 by constituents of fennel (Foeniculum vulgare): identification and characterization of a mechanism-based inactivator.
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DOI：
10.1021/jf0713253
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发表时间：
2007-11
影响因子：
6.1
通讯作者：
Subehan;S. F. Zaidi;S. Kadota;Y. Tezuka
中科院分区：
文献类型：
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作者：
Subehan;S. F. Zaidi;S. Kadota;Y. Tezuka
茴香，茴香的种子，被用作烹饪香料和传统药物。茴香甲醇提取物对人肝微粒体细胞色素P450 3A 4（CYP 3A 4）介导的红霉素N-去甲基化具有失活机制。本研究旨在鉴定具有抑制作用的茴香成分。从茴香的甲醇提取物中分离出13种化合物，并测试了它们对CYP 3A 4的抑制作用。其中，5-甲氧基补骨脂素（5-MOP）表现出最强的抑制作用，IC 50值为18.3 μ M，且为混合型抑制。此外，在预孵育时间为20 min时，只有5-MOP表现出预孵育时间依赖性; IC_（50）值从预孵育0 min时的18.3 μ M下降到预孵育20 min时的4.6 μ M。进一步研究表明，5-MOP具有时间依赖性抑制、需要NADPH、缺乏亲核试剂的保护作用、以及通过竞争性抑制剂恢复CYP 3A 4活性。这一结果表明，5-MOP对CYP 3A 4的抑制活性是一种基于机制的失活。基于机制的失活的动力学参数的特征在于KI值为15.0 μ M，kinact值为0.098 min（-1）。
Fennel, a seed of Foeniculum vulgare, is used as a culinary spice and traditional medicine. The methanolic extract of fennel showed a characteristic of mechanism-based inactivation on erythromycin N-demethylation mediated by human liver microsomal cytochrome P450 3A4 (CYP3A4). The present study was conducted to identify the fennel constituent having the inhibition. Thirteen compounds have been isolated from a methanol extract of fennel and tested for their inhibition on CYP3A4. Among them, 5-methoxypsoralen (5-MOP) showed the strongest inhibition with an IC50 value of 18.3 microM and a mixed type of inhibition. In addition, with the preincubation time of 20 min only 5-MOP showed preincubation time dependency; the IC50 value decreased from 18.3 microM with a preincubation time of 0 min to 4.6 microM with a preincubation time of 20 min. Further investigation on 5-MOP showed the characteristics of time-dependent inhibition, requirement of NADPH, lack of protecting effect of nucleophiles, and recovery of CYP3A4 activity by the competitive inhibitor. This result suggests that the inhibitory activity of CYP3A4 by 5-MOP was a mechanism-based inactivation. The kinetic parameter for mechanism-based inactivation was characterized by a KI value of 15.0 microM and a kinact value of 0.098 min(-1).